Oxidative stress occurs when active oxygen generated by an external or internal factor overwhelms the processing capacity of a living body. Active oxygen species (e.g., hydrogen peroxide, superoxide radical, and the like) are produced as a main product or by-product of various enzymatic reactions in cells. Although the living body is exposed to many oxidative stresses even under normal conditions, various antioxidation systems are fully used to maintain the homeostasis of the redox condition. When an excess of active oxygen, peroxides, and the like, or the collapse of an antioxidation system causes imbalance in the redox condition, the proteins, lipids, and DNAs become disordered and thereby various intracellular organs become disordered. Accordingly, oxidative stress is believed to be involved in many diseases, such as cancer, lifestyle-related disease, central nervous system disease, lung disease, heart disease, kidney disease, ischemic disease, diseases related to aging, and the like. Specific examples thereof include, without limitation, amyotrophic lateral sclerosis (ALS), Huntington disease, Parkinson disease, Alzheimer disease, Friedreich ataxia (FRDA), Creutzfeldt-Jakob disease, Machado-Joseph disease, spinocerebellar ataxia, multiple system atrophy (MS), atherosclerosis, myocardial infarction, cerebral infarction, senile cognition disorder, diabetes, alcoholic liver injury, non-alcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, hearing loss, and spinal muscular atrophy (SMA).
Meanwhile, mitochondria are one of the cell organelles in eukaryotic cells, and their main function is to supply ATP (adenosine triphosphate), which is energy necessary for cells to live. Moreover, since mitochondria are physiologically active oxygen sources under normal conditions, when an abnormality occurs in a function of the mitochondria, it is believed that a supply balance of active oxygen is disrupted to generate or increase oxidative stress. As described above, there is believed to be a close relationship between the mitochondria and oxidative stress.
For the above reasons, there is a possibility that various diseases including diseases related to mitochondrial dysfunction, such as mitochondrial disease, neurodegenerative disease, diseases related to aging, and the like, in addition to the above-described diseases, can be treated by suppressing oxidative stress (i.e., returning the balance of active oxygen/antioxidation system to normal). In some embodiments, diseases related to mitochondrial dysfunction include diseases such as amyotrophic lateral sclerosis (ALS), Huntington disease, Parkinson disease, Alzheimer disease, Friedreich ataxia (FRDA), Leber's hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh encephalopathy (Leigh Syndrome), Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy with ragged-red fibers (Fukuhara disease, MERRF, myoclonic epilepsy, myoclonic epilepsy syndrome), Pearson's disease (pancytopenia, multiple organ dysfunction syndrome), and the like. See, e.g., Kevin J. Bamham et al. Nature Drug Discovery 2004, 3, 205-214; Michael T. Linl et al. Nature 2006, 443, 787-795; Bayani Uttara et al. Current Neuropharmacology 2009, 7, 65-74; Toren Finkel et al. Nature 2000, 408, 239-247; Jiang et al. Translational Neurodegeneration 2015, 4, 14-19; Edens B. M., Miller N., and Ma Y. C. Front. Cell. Neurosci., 2016, 10, 44-59; and D. Simon et al. Journal of Neuroscience 2004, 24(8), 1987-1995.